Cancer is a group of diseases in which abnormal cells divide without control. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body. There are several main types of cancer. Carcinoma is cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the bloodstream. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system.
Several treatments are available for cancer, including surgery and radiation for localised disease, and drugs that destroy cancer cells (chemotherapy). Chemotherapy plays a significant part in cancer treatment, as it is required for the treatment of advanced cancers with distant metastasis and often helpful for tumour reduction before surgery (neoadjuvant therapy). It is also used following surgery or radiation (adjuvant therapy) to destroy any remaining cancer cells or prevent recurrence of the cancer.
Many anti-cancer drugs have been developed based on various modes of action: alkylating agents that act directly on the DNA (such as cisplatin, carboplatin, oxaliplatin, busulfan, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine); antimetabolites that interfere with DNA and RNA synthesis (such as 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine (ara-C), fludarabine); anthracyclines that interfere with enzymes involved in DNA replication (such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone); microtubule disrupters (taxanes such as paclitaxel and docetaxel or Vinca alkaloids such as vinblastine, vincristine, and vinorelbine); topoisomerase inhibitors (such as etoposide, doxorubicin, topotecan and irinotecan); hormone therapy (such as tamoxifen, flutamide) and recently introduced targeted therapy (such as the inhibitors of EGFR cetuximab, gefitinib or the protein tyrosine kinase inhibitor imatinib), are the most frequently used.
The development of chemotherapy in the last decades has significantly improved the treatment of cancer, resulting in effective treatments in some types of cancers, and improved survival or time to progression in others. Currently, most chemotherapy is administered intravenously; however, oral chemotherapy drugs are gaining wider use.
Unfortunately, most chemotherapy drugs cannot differentiate between a cancer cell and a healthy cell. Therefore, chemotherapy often affects the body's normal tissues and organs which results in complication of treatments, or side effects. In addition to the problems they cause, side effects can prevent doctors from delivering the prescribed dose of chemotherapy, reducing the probability of a correct treatment of cancer. Most frequent side effects of chemotherapy are anaemia, neutropaenia, thrombocytopaenia, fatigue, alopecia, nausea and vomiting, mucositis and pain.
One the side effects associated with some chemotherapeutic agents, especially with 5-fluorouracil and its prodrug capecitabine, is Palmar-Plantar Erythrodysesthesia (PPE), an erythematous eruption of the palms and soles also known as Hand Foot Syndrome (HFS). PPE is a distinctive and relatively frequent toxic reaction. It is a painful swelling and erythematous rash, located in the palms and soles, often preceded by dysesthesia, usually in the form of a tingling sensation, and often associated with oedema. The rash may become bollous and then desquamate without scarring, and pain gradually increases. Erythema may also occur in periungal areas. Generally it is confined to the hands and feet, the hands are usually more severely affected than the feet.
Histologically PPE shows mild spongiosis, scattered necrotic and dyskeratotic keratynocites and vacuolar degeneration of the basal layer. Dermal changes in most cases include dilated blood vessels, papillary edema, and a sparse superficial perivascular limphohistiocytic infiltrate that can be found in varying degrees in the epidermis.
PPE is clearly distinct from other adverse skin reactions and is reviewed in Nagore E. et al, Am J Clin Dermatol. 2000, 1(4), 225-234. Despite its frequency, little is known of its causes.
The advent of molecularly targeted therapies has changed the face of cancer treatment in the last few years. Among the targeted therapies for cancer, there has been a keen interest in developing agents that interfere with angiogenesis, the process by which new blood vessels are formed. By blocking the activity of receptors such as the platelet derived growth factor (PDGFR) or the vascular endothelial growth factor receptor (VEGFR), or by inhibiting members of their signalling pathways, tumour vessel formation can be halted and even reversed. Some of these targets are the ubiquitous mitogen-activated protein kinase (MAPK) pathway or Raf/MEK/ERK pathway, which controls the growth and survival of human tumours in proangiogenic pathways, which also involve signalling through MAPK. Solid tumours frequently exhibit activating oncogenic mutations in ras and/or overactivation of Raf-1 kinase, resulting in dysregulated signaling through the MAPK pathway, and consequent tumor cell proliferation and angiogenesis.
This rational approach to cancer treatment lead to the development of a second generation tyrosine kinase inhibitors that are able to target more that one target and pathways. Agents targeting multiple pathways in tumour growth are highly attractive, potentially offering the benefits of combined therapy within a single agent. The majority of these newer agents inhibit more than one receptor tyrosine kinase and may have unique inhibition profiles. Among the multitargeted kinase inhibitors (MKI's), sorafenib and sunitinib are already authorised for use, and vandetanib, motesanib, ABT-869 and several other compounds are still under development.
Sorafenib (Nexavar®) is an oral drug capable of inhibiting several receptor tyrosine kinases that are involved in tumour progression and angiogenesis. Sorafenib blocks Raf gene products (serine-threonine kinases), including mutated B-Raf, as well as platelet-derived growth factor-beta (PDGFR-β), FLt3, and vascular endothelial growth factor receptor-2 and -3 (VEGFR-2 and -3). Sorafenib has been approved by the FDA in 2005 and by the EMEA in 2006 for the treatment of metastatic renal cell carcinoma and advanced hepatocellular carcinoma.
Sunitinib (Sutent®) is also an oral drug, a multitargeted tyrosine kinase inhibitor that blocks VEGFR-1, -2, and -3, PDGFR-α and -β, Ret, c-Kit, and FLT3. In 2006 it has been approved by the FDA and by the EMEA for use in patients with gastrointestinal stromal tumor (GIST) who are refractory to or intolerant of imatinib mesylate, and in patients with metastatic renal cell carcinoma. It is usually administered in a 4 week-on, 2 week-off schedule, to allow patients to recover from some potential toxicities.
The MKI's such as sorafenib and sunitinib have side effects, the most frequent being fatigue, hypertension, nausea and diarrhea. Their safety profiles are however generally more favorable than those of many standard chemotherapies.
However, as with other tyrosine kinase inhibitors, MKI's are associated with significant dermatologic adverse reactions. Hand-Foot Skin Reaction (HFSR) is the most clinically significant (Rosenbaum S E et al. Support Care Cancer (2008) 16:557-566 “Dermatological reactions to the multitargeted tyrosine kinase inhibitor sunitinib”; Robert C et al J Am Acad Dermatol 2009, vol. 60 no. 2, 299-305 “Dermatological symptoms associated with the multikinase inhibitor sorafenib”).
Hand-Foot Skin Reaction (HFSR) is a distinct localized cutaneous reaction characterized by erythema, numbness, tingling and either dysesthesia or paresthesia, particularly on the palms and or soles. Histologically, it is characterized by thick, well defined hyperkeratotic lesions frequently affecting digital flexural location. It develops within the first 2-4 weeks of MKI administration. After several weeks the lesions, with or without blisters, are followed by areas of thickened or hyperkeratotic skin resembling skin calluses that are painful.
HFSR is described in: Lacouture M E et al. The Oncologist 2008, 13, no. 9, 1001-1011: “Evolving Strategies for the management of Hand-Foot Skin Reaction associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib”; Beldner M et al The Oncologist 2007 12:1178-1182 “Localized Palmar-Plantar epidermal hyperplasia: a previously undefined dermatological toxicity to sorafenib”; Yang C H et al. British journal of Dermatology 2008, 158 592-596 “Hand-Foot skin reaction in patients treated with sorafenib: a clinopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy”; Porta C et al. Clin Exp Med 2007, 7:12-134 “Uncovering Pandora's vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib”; Wood L. et al. Community Oncology 2010, vol. 7, no. 1 pages 23-29: “Practical Considerations in the Treatment of Hand Foot Skin Reaction caused by Multikinase Inhibitors”.
As explained in these publications, Hand-Foot Skin Reaction is distinguished clinically and histologically from palmar plantar erythrodysestesia (PPE) [also known as Hand-foot syndrome (HFS)], induced by chemotherapy such as 5-FU, capecitabine, or pegylated liposomal doxorubicine.
Both conditions show palmar-plantar localization, tenderness, pain and resolution of the toxicity upon discontinuation of the drug.
However, the typical pattern of localized hyperkeratotic lesions surrounded by erythematous areas distinguishes HFSR from PPE, in which symmetric paresthesias, diffusely tender erythema and oedema occur. Further, HFSR can affect non pressure-bearing areas, such as toes and finger webs, and the lateral sides of the soles. Pathologically, MKI's induce keratinocyte vacuolar degeneration in the stratum malpighii together with epidermal acanthosis, while PPE induced by chemotherapy shows dermal-epidermal interface dermatitis and vacuolar degeneration of basilar keratynocytes. The main histologic changes observed in HFSR suggest a defect in cell maturation, with modifications in keratinocyte differentiation, possibly increased apoptosis of this same cell population, as well as a specific inflammation. The rate of epidermal cell replication is markedly accelerated in active lesions of HFSR. The most relevant histopathological characteristic of HFSR is keratinocyte damage, present as intracytoplasmic eosinophilic bodies, unique to this condition. The mechanism by which HFSR originates is not known.
The incidence of HFSR is high. A meta-analysis has shown that the summary incidence of HFSR in patients treated with sorafenib was 33.8% for grades 1-3, and 8.9% for grade 3 (Chu D., Lacouture M E et al. Acta Oncologica 2008; 4 16-186: “Risk of Hand Foot Skin Reaction with Sorafenib: A systematic Review and Meta-Analysis”). With sunitinib, the summary incidence was calculated at 18.9% for grades 1-3 and 5.5% for grade 3 (Chu D. Lacouture M E, et al. Clinical Genitourinary Cancer 2009, no. 1 11-19: “Risk of Hand Foot Skin Reaction with the Multitargeted Kinase Inhibitor Sunitinib in patients with Renal Cell and Non-Renal Cell carcinoma: a Meta-analysis”). HFSR can negatively affect health-related quality of life and activities of daily living in patients being treated with MKI's such as sorafenib and sunitinib.
The severity of HFSR is most widely done using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 3.0). The clinical characteristics of each grade are:    1. Minimal skin changes or dermatitis (e.g. erythema) without pain    2. Skin changes (e.g. peeling, blisters, bleeding, oedema) or pain; no interference with patient activities of daily living;    3. Ulcerative dermatitis or skin changes with pain; interferes with patients activities of daily living.
It can also be graded using modified criteria which better fit with clinical practice (Porta C et al. Clin Exp Med 2007, 7:12-134):                1. numbness, dysaesthesia, paraesthesia, tingling, painless swelling, erythema or discomfort of hands or feet, which does not disrupt patient's normal activities;        2. One or more of the following symptoms: painful erythema, swelling, hyperkeratosis of the hands or feet, discomfort affecting the patient's normal activities;        3. One or more of the following symptoms: moist desquamation, ulceration, blistering, hyperkeratosis, severe pain of the hands and feet, severe discomfort that causes the patient to be unable to work or perform daily activities.        
There is at the moment no effective treatment for HFSR. Before treatment with MKI, removal of pre-existing hyperkeratotic areas and calluses is recommended. Once the skin reaction appears after initiating the treatment with MKI's, some of the few treatments that have been proposed are: cold compresses or ice packs, avoiding pressure on hands or feet; skin hydration; emollient skin creams, clobetasol ointment or topical analgesics. For the more severe grades (2-3), dose reduction or interruption of the treatment with MKI's is recommended. Urea, fluorouracil and tazarotene creams have also been mentioned, since these agents inhibit keratinocyte proliferation (Lacouture M E et al. The Oncologist 2008, vol. 13, no. 9, 1001-1011: “Evolving Strategies for the management of Hand-Foot Skin Reaction associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib”, Anderson et al. The Oncologist 2009, vol. 14, no. 3, 291-302: “Search for evidence-based approaches for the prevention and palliation of Hand-foot Skin Reaction (HFSR) caused by the Multikinase Inhibitors”); Wood L. et al. Community Oncology 2010, vol. 7, no. 1 pages 23-29: “Practical Considerations in the Treatment of Hand Foot Skin Reaction caused by Multikinase Inhibitors”).
None of the proposed treatments has yet been able to effectively treat or prevent HFSR. This is a serious problem for the patient, because besides the intrinsic discomfort and pain, in advanced grades it implies in a reduction or interruption of the chemotherapy with MKI's, which affects the survival and/or time to progression of the cancer being treated. It is clear that an effective treatment of HFSR is still needed, in order to untie the full potential of multikinase inhibitors and the different regimens and combinations in which they are and will be used.
Allopurinol is a structural isomer of hypoxanthine, it inhibits xanthine oxidase, an enzyme that converts oxypurines to uric acid. By blocking the production of uric acid, this agent decreases serum and urine concentrations of uric acid, thereby providing protection against uric acid-mediated end organ damage in conditions associated with excessive production of uric acid. It has been used for many years for the treatment or prevention of gout, hyperuricemia and kidney stones, through oral or parenteral systemic administration.
Allopurinol has also been reported for the treatment of mucositis, a frequent chemotherapy- or radiation-induced damage to the rapidly dividing cells lining the mouth, throat and gastrointestinal (GI) tract. Allopurinol is used in the form of mouthwashes (dispersion in water) (Porta C. et al, Am J clin Oncol. 1994, Vol 17, no. 3, 246-247). An improved formulation for mouthwashes comprising allopurinol, carboxymethylcellulose and water is described in JP-3106817. Hanawa et al. in Drug Dev Ind Pharm 2004, 30(2) 151-161 describe another mouthwash comprising allopurinol, polyethyleneoxide and carrageenan. Kitagawa et al. in J Radiation Research 2008, vol. 49, no. 1, 49-54, describe that Allopurinol gel mitigates radiation-induced mucositis and dermatitis in rats. Dagher et al., Canadian Journal of Hospital Pharmacy, vol. 40, no. 5 1987, page 189, discloses the use of allopurinol mouthwash and vaginal 0.1% cream for the treatment of 5-FU induced mucositis.
WO94/05293 and WO94/05291 describe synergistic compositions comprising methylsuphonylmethane (MSM) and at least one of oxypurinol or allopurinol and their use for the treatment of skin conditions, diseases and injuries such as burns, dermatitis, hyperkeratosis, sun exposure, skin ageing, etc. Oxypurinol and allopurinol are described as enhancing the skin healing or repairing properties of MSM.
W02007/138103 discloses and exemplifies the use of allopurinol, in particular topically in the form of a cream for the treatment of Palmar Plantar Erythrodysesthesia or Hand-Foot syndrome induced by fluoropyrimidine chemotherapy (5-FU and capecitabine). However, the skilled person knows that fluoropyrimidine and Multitargeted kinase inhibitors act at a molecular level by a very different mechanism, and their skin toxicities are different, both clinically and histologically, as discussed above.
Indeed, a interdisciplinary panel of experts in Wood et al. (Community Oncology) state at page 1 that:
“MKI-associated HFSR is a clinically and pathologically distinct skin toxicity from the HFS seen with older chemotherapeutic agents.”
None of the cited documents mentions or suggests that allopurinol would be useful for the treatment or prevention of Hand-Foot Skin Reaction (HFSR).